Clonally expanded, thyrotoxic effector CD8 + T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis

• Published in: Science translational medicine 2023-05, Vol.15 (696), p.eadg0675
• Main Authors: Lechner, Melissa G, Zhou, Zikang, Hoang, Aline T, Huang, Nicole, Ortega, Jessica, Scott, Lauren N, Chen, Ho-Chung, Patel, Anushi Y, Yakhshi-Tafti, Rana, Kim, Kristy, Hugo, Willy, Famini, Pouyan, Drakaki, Alexandra, Ribas, Antoni, Angell, Trevor E, Su, Maureen A
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes - metabolism; Hashimoto Disease; Humans; Interleukins; Thyroiditis - chemically induced; Thyroiditis - immunology; Thyroiditis, Autoimmune - genetics; Thyroiditis, Autoimmune - pathology
• ISSN: 1946-6234; 1946-6242; 1946-6242
• DOI: 10.1126/scitranslmed.adg0675

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6 CD8 T cells (effector CD8 T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (T ) and T peripheral helper (T ) cells, as a driver of these thyrotoxic effector CD8 T cells. In the presence of IL-21, human CD8 T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.